1. Field of the Invention
The present invention relates to a method for producing a high-concentration eicosapentaenoic acid or the ester derivative thereof, more specifically to a new method of producing, at high efficiency, a high-concentration form of eicosapentaenoic acid (EPA) or the ester derivative thereof which is effective as a prescription medicine for the prevention of thrombosis and for the medical treatment and prevention of thrombus-induced diseases.
2. Description of Related Art
Eicosapentaenoic acid (EPA), and the ester, amide or other derivatives thereof, have been conventionally known as being effective as a prescription medicine for the prevention of thrombosis and for the medical treatment of thrombus-induced diseases.
It is known that eicosapentaenoic acid (EPA) and the derivatives thereof are contained per se, or in the form of a glyceride and other derivatives thereof, in natural fats and oils, particularly in fats and oils of mackerel, sardine, cod and other marine products. Studies have been made concerning the methods for taking out eicosapentaenoic acid from these fish oils.
However, these oils contain an overwhelming quantity of fatty acids with a carbon number of less than 19 and more than 21, i.e. other than eicosapentaenoic acid, which is an unsaturated fatty acid with a carbon number of 20. This makes it exceedingly difficult to efficiently and selectively purify eicosapentaenoic acid alone as a high-concentration (high purity) product.
For example, a method has been proposed in which fatty acid mixtures from natural fats and oils are esterified, and subjected to precision fraction under reduced pressures and the resultant fraction is purified with a urea addition method to provide eicosapentaenoic acid from the natural fats and oils (Japanese Patent Provisional Publication No. 149400/82).
By this method, in which fatty acid mixtures from natural fats and oils are subjected to precision fraction under a reduced pressures of 10 mmHg, preferably of 0.1 to 0.01 mmHg at a single rectifying column filled with rings and the resulting products are rectified by the urea addition method, eicosapentaenoic acid in a concentration of some 80% can be obtained. By this method, however, a mere 30% of eicosapentaenoic acid ester exists in the C.sub.20 fraction are obtained by the rectification. Such methods also requires complicated trouble-some treatment processes, such as a treatment of the urea adduct and the subsequent distillation under reduced pressures. Even with these processes, it is exceedingly difficult to improve the concentration of the eicosapentaenoic acid ester to 85% or higher. Thus, by the foregoing method large quantities of and urea, a multiplicity of treatments with urea, become practically required, placing great limitations on the reduction of manufacturing costs as well as the improvement of production efficiency. There has therefore been a serious limitation to putting this method into practical application.
Almost concurrently with the above method, a method was proposed by the applicant of the present invention wherein two distillation columns are employed to subject fatty acid mixtures obtained from natural fats and oils to continuous distillation to provide approximately 50% eicosapentaenoic acid as the C.sub.20 fraction, then the product is subjected to urea addition treatment and purification through column chromatography (Japanese Patent Provisional Publication No. 8037/1983). This improved method has substantially enhanced the efficiency of purifying EPA by a distillation process, but eicosapentaenoic acid and the ester derivative thereof still cannot be obtained in concentration (or purity) as high as 80% or more without the subsequent urea addition treatments. Even with the urea addition process, the method still remains unsuccessful in producing eicosapentaenoic acid and the ester derivative thereof in a concentration as high as 85% or higher. For this reason, there has been need for improvements in the purification process of EPA and its ester derivatives.
In order to produce eicosapentaenoic acid and the ester derivative thereof, effective as a medical prescription medicine, or for clinical purposes it is strongly desired to purify it in a concentration of 80% or more, preferably 85% or more in large quantities and at high efficiency. Yet, under the aforestated circumstances and such methods object has been unfulfilled.